IL-1α comes to the fore

Credit: NPG

The uncontrolled inflammasome-mediated processing of interleukin-1β (IL-1β) can lead to the development of autoinflammatory disorders. Now, Lukens et al. report that, in the absence of a fully active SH2 domain-containing protein tyrosine phosphatase 1 (SHP1; also known as PTPN6), IL-1α can also promote autoinflammatory responses and that this effect is independent of inflammasome activation.

SHP1 is a negative regulator of immune signalling, and inactivating mutations in PTPN6 have been associated with autoimmune and inflammatory disorders in both humans and mice. The authors studied Ptpn6^spin mutant mice, which suffer from chronic footpad inflammation as a result of a hypomorphic Ptpn6 mutation. This inflammatory phenotype appeared from 8 weeks of age and was not associated with early developmental or functional immune cell defects. It was only after the onset of disease that the numbers of myeloid cells and T cells, as well as the levels of pro-inflammatory cytokines, were enhanced in the draining popliteal lymph nodes of these mice.

compromised SHP1 activity is associated with inflammasome-independent IL-1α-mediated auto-inflammation

Interestingly, the autoinflammatory phenotype of Ptpn6^spin mice was not rescued by the genetic ablation of the inflammasome components NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3), caspase 1 and caspase 11. By contrast, the genetic deletion of IL-1α was sufficient to prevent footpad inflammation in Ptpn6^spin mice. Moreover, in these mice, the absence of IL-1α expression enabled wound healing following microabrasion-induced footpad injury and promoted recovery from acetaminophen-induced liver damage, whereas tissue damage-induced inflammation failed to be controlled when IL-1α was expressed. Thus, compromised SHP1 activity is associated with inflammasome-independent IL-1α-mediated autoinflammation.

Next, experiments using bone marrow chimaeras showed that the expression of fully active SHP1 in haematopoietic cells is essential for the control of IL-1α-mediated autoinflammatory responses. Furthermore, receptor-interacting protein 1 (RIP1; also known as RIPK1) was found to contribute to inflammation downstream of hypoactive SHP1. Indeed, the pharmacological inhibition of RIP1 was sufficient to reduce the levels of IL-1α and other pro-inflammatory mediators in diseased Ptpn6^spin mice. In addition, RIP1-deficient (but not RIP1-expressing) haematopoietic cells from Ptpn6^spin mice failed to establish chronic inflammation in wild-type recipients.

RIP1 has been shown either to promote the activation of extracellular signal-regulated kinase (ERK) and nuclear factor-κB (NF-κB), or, together with RIP3, to initiate programmed necrosis (which is a pro-inflammatory type of cell death). RIP3 was found to be dispensable for the development of chronic inflammation in Ptpn6^spin mice. By contrast, ERK and NF-κΒ activity contributed to the autoinflammatory phenotype of Ptpn6^spin mice, which indicates that RIP1-induced pro-inflammatory signalling and IL-1α might be potential therapeutic targets in autoinflammatory disorders.