The Critical Role of Chemokine (C-C Motif) Receptor 2-Positive Monocytes in Autoimmune Cholangitis.

The therapy of primary biliary cholangitis (PBC) has lagged behind other autoimmune diseases despite significant improvements in our understanding of both immunological and molecular events that lead to loss of tolerance to the E2 component of pyruvate dehydrogenase, the immunodominant autoepitope of PBC. It is well known that Ly6Chi monocytes are innate immune cells infiltrating inflammatory sites that are dependent on the expression of C-C motif chemokine receptor 2 (CCR2) for emigration from bone marrow. Importantly, humans with PBC have a circulating monocyte pro-inflammatory phenotype with macrophage accumulation in portal tracts. We have taken advantage of an inducible chemical xenobiotic model of PBC and recapitulated the massive infiltration of monocytes to portal areas. To determine the clinical significance, we immunized both CCR2-deficient mice and controls with 2OA-BSA and noted that CCR2 deficiency is protective for the development of autoimmune cholangitis. Importantly, because of the therapeutic potential, we focused on inhibiting monocyte infiltration through the use of cenicriviroc (CVC), a dual chemokine receptor CCR2/CCR5 antagonist shown to be safe in human trials. Importantly, treatment with CVC resulted in amelioration of all aspects of disease severity including serum total bile acids, histological severity score, and fibrosis stage. In conclusion, our results indicate a major role for Ly6Chi monocytes and for CCR2 in PBC pathogenesis and suggest that inhibition of this axis by CVC should be explored in humans through the use of clinical trials.

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

Eosinophilia is a hallmark characteristic of T helper type 2 (TH2) cell-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 receptors PIR-A and PIR-B. Upon self-recognition of ß2-microglobulin (ß2M) molecules, PIR-B served as a permissive checkpoint for IL-5-induced development of eosinophils by suppressing the proapoptotic activities of PIR-A, which were mediated by the Grb2-Erk-Bim pathway. PIR-B-deficient bone marrow eosinophils underwent compartmentalized apoptosis, resulting in decreased blood eosinophilia in naive mice and in mice challenged with IL-5. Subsequently, Pirb(-/-) mice displayed impaired aeroallergen-induced lung eosinophilia and induction of lung TH2 cell responses. Collectively, these data uncover an intrinsic, self-limiting pathway regulating IL-5-induced expansion of eosinophils, which has broad implications for eosinophil-associated diseases.

Paired immunoglobulin-like receptor-B inhibits pulmonary fibrosis by suppressing profibrogenic properties of alveolar macrophages.

Macrophages are lung-resident cells that play key roles in fibrosis. Surprisingly, pathways that inhibit macrophage functions, especially in idiopathic pulmonary fibrosis (IPF), receive little attention. The cell-surface molecule paired immunoglobulin-like receptor B (PIR-B) can suppress macrophage activation. However, its role in pulmonary fibrosis remains unknown. We sought to define the role of PIR-B in IPF. The expression of PIR-B was assessed (by quantitative PCR and flow cytometry) after bleomycin treatment. Differential cell counts, histopathology, and profibrogenic-mediator expression, for example, collagen, α-smooth muscle actin, resistin-like molecule-α (Relm-α), matrix metalloproteinase (MMP)-12, and tissue inhibitor of metalloproteinase (TIMP)-1, were determined (by ELISA quantitative PCR and flow cytometry) in the lungs of wild-type and Pirb(-/-) mice after bleomycin or IL-4 treatment. Bone marrow-derived wild-type and Pirb(-/-) macrophages were stimulated with IL-4 and assessed for Relm-α and MMP-12 expression. PIR-B was up-regulated in lung myeloid cells after bleomycin administration. Bleomycin-treated Pirb(-/-) mice displayed increased lung histopathology and an increased expression of collagen and of the IL-4-associated profibrogenic markers Relm-α, MMP-12, TIMP-1, and osteopontin, which were localized to alveolar macrophages. Increased profibrogenic mediator expression in Pirb(-/-) mice was not attributable to increased IL-4/IL-13 concentrations, suggesting that PIR-B negatively regulates IL-4-induced macrophage activation. Indeed, IL-4-treated Pirb(-/-) mice displayed increased Relm-α expression and Relm-α(+) macrophage concentrations. IL-4-activated Pirb(-/-) macrophages displayed increased Relm-α and MMP-12 induction. Finally, leukocyte immunoglobulin-like receptor subfamily B member 3 (LILRB3)/immunoglobulin-like transcript-5, the human PIR-B orthologue, was expressed and up-regulated in lung biopsies from patients with IPF. Our results establish a key role for PIR-B in IPF, likely via the regulation of macrophage activation. Therefore, PIR-B/LILRB3 may offer a possible target for suppressing macrophage profibrogenic activity in IPF.