Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Origin and physiological roles of inflammation

Abstract

Inflammation underlies a wide variety of physiological and pathological processes. Although the pathological aspects of many types of inflammation are well appreciated, their physiological functions are mostly unknown. The classic instigators of inflammation — infection and tissue injury — are at one end of a large range of adverse conditions that induce inflammation, and they trigger the recruitment of leukocytes and plasma proteins to the affected tissue site. Tissue stress or malfunction similarly induces an adaptive response, which is referred to here as para-inflammation. This response relies mainly on tissue-resident macrophages and is intermediate between the basal homeostatic state and a classic inflammatory response. Para-inflammation is probably responsible for the chronic inflammatory conditions that are associated with modern human diseases.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Causes, and physiological and pathological outcomes, of inflammation.
Figure 2: The inflammatory pathway.
Figure 3: Cell death and its consequences.
Figure 4: Three modes of adaptation and maintenance of tissue homeostasis.

References

  1. Majno, G. & Joris, I. Cells, Tissues and Disease (Oxford Univ. Press, 2004).

    Google Scholar 

  2. Kumar, V., Cotran, R. S. & Robbins, S. L. Robbins Basic Pathology (Saunders, 2003).

    Google Scholar 

  3. Barton, G. M. A calculated response: control of inflammation by the innate immune system. J. Clin. Invest. 118, 413–420 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  4. Pober, J. S. & Sessa, W. C. Evolving functions of endothelial cells in inflammation. Nature Rev. Immunol. 7, 803–815 (2007).

    CAS  Article  Google Scholar 

  5. Nathan, C. Neutrophils and immunity: challenges and opportunities. Nature Rev. Immunol. 6, 173–182 (2006).

    CAS  Article  Google Scholar 

  6. Nathan, C. Points of control in inflammation. Nature 420, 846–852 (2002).

    ADS  CAS  PubMed  Article  Google Scholar 

  7. Serhan, C. N. & Savill, J. Resolution of inflammation: the beginning programs the end. Nature Immunol. 6, 1191–1197 (2005).

    CAS  Article  Google Scholar 

  8. Serhan, C. N. Resolution phase of inflammation: novel endogenous anti-inflammatory and proresolving lipid mediators and pathways. Annu. Rev. Immunol. 25, 101–137 (2007).

    CAS  PubMed  Article  Google Scholar 

  9. Drayton, D. L., Liao, S., Mounzer, R. H. & Ruddle, N. H. Lymphoid organ development: from ontogeny to neogenesis. Nature Immunol. 7, 344–353 (2006).

    CAS  Article  Google Scholar 

  10. Medzhitov, R. & Janeway, C. A. Jr Innate immunity: the virtues of a nonclonal system of recognition. Cell 91, 295–298 (1997).

    CAS  PubMed  Article  Google Scholar 

  11. Mariathasan, S. et al. Cryopyrin activates the inflammasome in response to toxins and ATP. Nature 440, 228–232 (2006). This study shows that pore-forming exotoxins activate the NALP3 inflammasome.

    ADS  CAS  PubMed  Article  Google Scholar 

  12. Sokol, C. L., Barton, G. M., Farr, A. G. & Medzhitov, R. A mechanism for the initiation of allergen-induced T helper type 2 responses. Nature Immunol. 9, 310–318 (2008).

    CAS  Article  Google Scholar 

  13. Rakoff-Nahoum, S., Paglino, J., Eslami-Varzaneh, F., Edberg, S. & Medzhitov, R. Recognition of commensal microflora by Toll-like receptors is required for intestinal homeostasis. Cell 118, 229–241 (2004).

    CAS  PubMed  Article  Google Scholar 

  14. Turer, E. E. et al. Homeostatic MyD88-dependent signals cause lethal inflammation in the absence of A20. J. Exp. Med. 205, 451–464 (2008). This paper shows that the activation of TLRs by commensal microorganisms can result in lethal inflammation in the absence of a negative regulator of TLR signalling.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. Rizki, T. M. & Rizki, R. M. Lamellocyte differentiation in Drosophila larvae parasitized by Leptopilina . Dev. Comp. Immunol. 16, 103–110 (1992).

    CAS  PubMed  Article  Google Scholar 

  16. Dostert, C. et al. Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica. Science 320, 674–677 (2008). This study shows that environmental particles can trigger inflammation through the NALP3 inflammasome.

    ADS  CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. Rock, K. L. & Kono, H. The inflammatory response to cell death. Annu. Rev. Pathol. 3, 99–126 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. Bianchi, M. E. DAMPs, PAMPs and alarmins: all we need to know about danger. J. Leukoc. Biol. 81, 1–5 (2007).

    CAS  PubMed  Article  Google Scholar 

  19. Julius, D. & Basbaum, A. I. Molecular mechanisms of nociception. Nature 413, 203–210 (2001).

    ADS  CAS  PubMed  Article  Google Scholar 

  20. Park, J. S. et al. High mobility group box 1 protein interacts with multiple Toll-like receptors. Am. J. Physiol. Cell Physiol. 290, C917–C924 (2006).

    CAS  PubMed  Article  Google Scholar 

  21. Hofmann, M. A. et al. RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides. Cell 97, 889–901 (1999).

    CAS  PubMed  Article  Google Scholar 

  22. Vogl, T. et al. Mrp8 and Mrp14 are endogenous activators of Toll-like receptor 4, promoting lethal, endotoxin-induced shock. Nature Med. 13, 1042–1049 (2007).

    CAS  PubMed  Article  Google Scholar 

  23. Keller, M., Ruegg, A., Werner, S. & Beer, H. D. Active caspase-1 is a regulator of unconventional protein secretion. Cell 132, 818–831 (2008). This study shows that caspase 1 regulates the secretion of many cytosolic proteins by a non-canonical (ER–Golgi-independent) mechanism.

    CAS  PubMed  Article  Google Scholar 

  24. Chen, G. et al. Bacterial endotoxin stimulates macrophages to release HMGB1 partly through CD14- and TNF-dependent mechanisms. J. Leukoc. Biol. 76, 994–1001 (2004).

    CAS  PubMed  Article  Google Scholar 

  25. Pull, S. L., Doherty, J. M., Mills, J. C., Gordon, J. I. & Stappenbeck, T. S. Activated macrophages are an adaptive element of the colonic epithelial progenitor niche necessary for regenerative responses to injury. Proc. Natl Acad. Sci. USA 102, 99–104 (2005).

    ADS  CAS  PubMed  Article  Google Scholar 

  26. Vermeer, P. D. et al. Segregation of receptor and ligand regulates activation of epithelial growth factor receptor. Nature 422, 322–326 (2003).

    ADS  CAS  PubMed  Article  Google Scholar 

  27. Martinon, F., Petrilli, V., Mayor, A., Tardivel, A. & Tschopp, J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440, 237–241 (2006). This study shows that uric acid (urate) crystals induce inflammation by activating the NALP3 inflammasome.

    ADS  CAS  PubMed  Article  Google Scholar 

  28. Brownlee, M., Cerami, A. & Vlassara, H. Advanced glycosylation end products in tissue and the biochemical basis of diabetic complications. N. Engl. J. Med. 318, 1315–1321 (1988). This paper describes AGEs and their role in inflammation.

    CAS  PubMed  Article  Google Scholar 

  29. Yan, S. F. et al. The biology of RAGE and its ligands: uncovering mechanisms at the heart of diabetes and its complications. Curr. Diab. Rep. 7, 146–153 (2007).

    CAS  PubMed  Article  Google Scholar 

  30. Navab, M. et al. Mechanisms of disease: proatherogenic HDL — an evolving field. Nature Clin. Pract. Endocrinol. Metab. 2, 504–511 (2006).

    ADS  CAS  Article  Google Scholar 

  31. Jiang, D. et al. Regulation of lung injury and repair by Toll-like receptors and hyaluronan. Nature Med. 11, 1173–1179 (2005). This study shows the protective role of TLR-induced tissue repair in sterile tissue injury.

    CAS  PubMed  Article  Google Scholar 

  32. Jiang, D., Liang, J. & Noble, P. W. Hyaluronan in tissue injury and repair. Annu. Rev. Cell Dev. Biol. 23, 435–461 (2007).

    CAS  PubMed  Article  Google Scholar 

  33. Higgs, G. A., Moncada, S. & Vane, J. R. Eicosanoids in inflammation. Ann. Clin. Res. 16, 287–299 (1984).

    CAS  PubMed  Google Scholar 

  34. Turnbull, A. V. & Rivier, C. L. Regulation of the hypothalamic–pituitary–adrenal axis by cytokines: actions and mechanisms of action. Physiol. Rev. 79, 1–71 (1999).

    CAS  PubMed  Article  Google Scholar 

  35. Cannon, W. Organization for physiological homeostasis. Physiol. Rev. 9, 399–431 (1929). This classic theoretical paper and review describes the principles of homeostatic control.

    Article  Google Scholar 

  36. Zong, W. X. & Thompson, C. B. Necrotic death as a cell fate. Genes Dev. 20, 1–15 (2006).

    CAS  PubMed  Article  Google Scholar 

  37. Huang, H. & Tindall, D. J. Dynamic FoxO transcription factors. J. Cell Sci. 120, 2479–2487 (2007).

    CAS  PubMed  Article  Google Scholar 

  38. Ghosh, S. & Karin, M. Missing pieces in the NF-κB puzzle. Cell 109, S81–S96 (2002).

    CAS  PubMed  Article  Google Scholar 

  39. Zong, W. X., Ditsworth, D., Bauer, D. E., Wang, Z. Q. & Thompson, C. B. Alkylating DNA damage stimulates a regulated form of necrotic cell death. Genes Dev. 18, 1272–1282 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. Gordon, S. & Taylor, P. R. Monocyte and macrophage heterogeneity. Nature Rev. Immunol. 5, 953–964 (2005).

    CAS  Article  Google Scholar 

  41. Hume, D. A. The mononuclear phagocyte system. Curr. Opin. Immunol. 18, 49–53 (2006).

    CAS  PubMed  Article  Google Scholar 

  42. Kanda, H. et al. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J. Clin. Invest. 116, 1494–1505 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. Ceradini, D. J. & Gurtner, G. C. Homing to hypoxia: HIF-1 as a mediator of progenitor cell recruitment to injured tissue. Trends Cardiovasc. Med. 15, 57–63 (2005).

    CAS  PubMed  Article  Google Scholar 

  44. Mantovani, A. et al. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 25, 677–686 (2004).

    CAS  PubMed  Article  Google Scholar 

  45. Gordon, S. Alternative activation of macrophages. Nature Rev. Immunol. 3, 23–35 (2003).

    CAS  Article  Google Scholar 

  46. Condeelis, J. & Pollard, J. W. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell 124, 263–236 (2006).

    CAS  PubMed  Article  Google Scholar 

  47. Majno, G. & Joris, I. Apoptosis, oncosis, and necrosis. An overview of cell death. Am. J. Pathol. 146, 3–15 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Fink, S. L. & Cookson, B. T. Apoptosis, pyroptosis, and necrosis: mechanistic description of dead and dying eukaryotic cells. Infect. Immun. 73, 1907–1916 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. Rothlin, C. V., Ghosh, S., Zuniga, E. I., Oldstone, M. B. & Lemke, G. TAM receptors are pleiotropic inhibitors of the innate immune response. Cell 131, 1124–1136 (2007).

    CAS  PubMed  Article  Google Scholar 

  50. Henson, P. M. & Hume, D. A. Apoptotic cell removal in development and tissue homeostasis. Trends Immunol. 27, 244–250 (2006).

    CAS  PubMed  Article  Google Scholar 

  51. Ravichandran, K. S. & Lorenz, U. Engulfment of apoptotic cells: signals for a good meal. Nature Rev. Immunol. 7, 964–974 (2007).

    CAS  Article  Google Scholar 

  52. Werner, S. & Grose, R. Regulation of wound healing by growth factors and cytokines. Physiol. Rev. 83, 835–870 (2003).

    CAS  PubMed  Article  Google Scholar 

  53. Tedgui, A. & Mallat, Z. Cytokines in atherosclerosis: pathogenic and regulatory pathways. Physiol. Rev. 86, 515–581 (2006).

    CAS  PubMed  Article  Google Scholar 

  54. Hotamisligil, G. S. Inflammation and metabolic disorders. Nature 444, 860–867 (2006).

    ADS  CAS  Article  PubMed  Google Scholar 

  55. Karin, M., Lawrence, T. & Nizet, V. Innate immunity gone awry: linking microbial infections to chronic inflammation and cancer. Cell 124, 823–835 (2006).

    CAS  PubMed  Article  Google Scholar 

  56. Stearns, S. & Koella, J. Evolution in Health and Disease (Oxford Univ. Press, 2008).

    Google Scholar 

  57. Gould, S. J. & Lewontin, R. C. The spandrels of San Marco and the Panglossian paradigm: a critique of the adaptationist programme. Proc. R Soc. Lond. B 21, 581–598 (1979).

    ADS  Google Scholar 

Download references

Acknowledgements

I apologize to the many authors whose work could not be cited directly because of space limitations. I thank I. Brodsky, T. Horng, A. Iwasaki, E. Kopp, N. Palm and D. Stetson for critical reading of the manuscript. R.M. is an investigator of the Howard Hughes Medical Institute.

Author information

Authors and Affiliations

Authors

Ethics declarations

Competing interests

The author declares no competing financial interests.

Additional information

Reprints and permissions information is available at http://www.nature.com/reprints.

Correspondence should be addressed to the author (ruslan.medzhitov@yale.edu).

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Medzhitov, R. Origin and physiological roles of inflammation. Nature 454, 428–435 (2008). https://doi.org/10.1038/nature07201

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature07201

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing