Paired immunoglobulin-like receptor A is an intrinsic, self-limiting suppressor of IL-5–induced eosinophil development

Abstract

Summary Eosinophilia is a hallmark characteristic of TH2-associated diseases and is critically regulated by the central eosinophil growth factor interleukin 5 (IL-5). Here we demonstrate that IL-5 activity in eosinophils was regulated by paired immunoglobulin-like receptor (PIR)-A and PIR-B. Upon self-recognition of β2M molecules, PIR-B served as a permissive checkpoint for IL-5-induced eosinophil development by suppressing the pro-apoptotic activities of PIR-A, which were mediated by the Grb2-Erk-Bim pathway. PIR-B-deficient bone marrow (BM) eosinophils underwent compartmentalized apoptosis, resulting in decreased blood eosinophilia in naïve, IL-5- and aeroallergen-challenged mice. Subsequently, Pirb−/− mice displayed impaired aeroallergen-induced lung eosinophilia and induction of lung TH2 responses. Collectively, these data uncovers an intrinsic, self-limiting pathway regulating IL-5-induced eosinophil expansion, which has broad implications for eosinophil-associated diseases.

Interleukin‐33 requires CMRF35‐like molecule‐1 expression for induction of myeloid cell activation

“…Thus, Clm1 À/À eosinophils are hypersensitive to eotaxin stimulation and even low amounts of eotaxins could induce a strong chemotactic response. Taken together, our data suggest that similar to other ITIMbearing receptors such as PIR-B, which can regulate multiple cellular responses (e.g., chemotaxis, differentiation, innate immune responses, and adhesion) (45)(46)(47)(48)(49), CLM-1 may regulate a broader range of eosinophil responses and effector functions.…”

Eosinophilic Gastroenteritis and Colitis: a Comprehensive Review

“…The ability to impede necrosis or redirect cell death from necrosis to apoptosis may lead to improved therapies in patients with eosinophilic conditions [137]. Ben Baruch-Morgenstern et al recently demonstrated that IL-5 activity in eosinophils was regulated by paired immunoglobulinlike receptors A and B, which may offer a way of regulating IL-5-induced expansion of the eosinophil [138]. CCchemokine receptor 3 (CCR3) is an eotaxin receptor known to be involved in eosinophil chemotaxis.…”

The Expanding Spectrum of Ligands for Leukocyte Ig-like Receptors

“…Furthermore, PIRA also binds to Nogo, although the binding strength is 10-fold less and only detected for the third to sixth domains. The functional importance of the interaction with PIRA with Nogo has not been determined, but some functions of PIRA are known, such as regulating cytokine-driven maturation of eosinophils (66), providing some idea of the possibilities. The measured interaction with PIRA also begs the question of which other LILRs might interact with the NogoR ligands as well.…”