DCIR Maintains Bone Homeostasis by Regulating IFN-γ Production in T Cells

Abstract

Dendritic cell immunoreceptor (DCIR) is a C-type lectin receptor mainly expressed in DCs. Dcir−/− mice spontaneously develop autoimmune enthesitis and ankylosis accompanied by fibrocartilage proliferation and ectopic ossification. However, the mechanisms of new bone/cartilage formation in Dcir−/− mice remain to be elucidated. In this study, we show that DCIR maintains bone homeostasis by regulating IFN-γ production under pathophysiological conditions. DCIR deficiency increased bone volume in femurs and caused aberrant ossification in joints, whereas these symptoms were abolished in Rag2−/−Dcir−/− mice. IFN-γ–producing T cells accumulated in lymph nodes and joints of Dcir−/− mice, and purified Dcir−/− DCs enhanced IFN-γ+ T cell differentiation. The ankylotic changes and bone volume increase were suppressed in the absence of IFN-γ. Thus, IFN-γ is a positive chondrogenic and osteoblastogenic factor, and DCIR is a crucial regulator of bone metabolism; consequently, both factors are potential targets for therapies directed against bone metabolic diseases.

Absence of DCIR1 reduces the mortality rate of endotoxemic hepatitis in mice

“…We have studied the roles of DCIR1 during aging and in several disease models. Among these, DCIR1 is involved in the suppression of autoimmune enthesitis with increasing age and EAE . However, in DSS‐induced colitis and endotoxemic hepatitis (present study), DCIR1 exacerbated the symptoms.…”

“…However, in DSS‐induced colitis and endotoxemic hepatitis (present study), DCIR1 exacerbated the symptoms. In the autoimmune enthesitis and EAE models, the main effector cells are T cells , suggesting the intervention of antigen‐specific immune responses. We have reported that lack of DCIR1 enhanced GM‐CSF signaling, resulting in an increase of DCs that effectively induced antigen specific IFN‐γ‐producing T cells .…”

“…DCIR polymorphism has also been involved in susceptibility for systemic lupus erythematosus and primary Sjogren's syndrome and in regulatory T‐cell induction after intravenous treatment with immunoglobulin to alleviate allergic airways disease . Furthermore, we have reported that Dcir1 ‐deficient ( Dcir1 −/− ) mice tend to develop autoimmune enthesitis with increased bone/cartilage formation with age, type II collagen‐induced experimental arthritis , and EAE . However, Dcir1 −/− mice showed lower susceptibility to dextran sulfate sodium (DSS)‐induced colitis , and experimental cerebral malaria than WT mice did .…”

C-type lectin receptor DCIR modulates immunity to tuberculosis by sustaining type I interferon signaling in dendritic cells

“…Further work is needed to understand the many roles of type I IFNs in TB, as suggested by a recent study showing that these cytokines can be protective or detrimental depending on the stage of M. tuberculosis infection (33) and on the M. tuberculosis strain (34). Interestingly, previous studies reported that DCIR-KO animals tend to develop more autoimmune CD4 + T cell-associated (Th1-or Th17-associated) pathologies (14,15). Based on our findings, it is likely that these phenotypes rely on an increased IL-12 production through impaired type I IFN signaling, which was not investigated in these cases.…”

“…DCIR is a rare case of a CLR that contains an immunoreceptor tyrosine-based inhibitory motif (ITIM) in its cytoplasmic tail and, as such, is generally believed to mediate inhibitory signals in DCs. In line with this concept, antibody-mediated DCIR triggering in human DCs inhibits TLR-mediated production of IL-1β, IL-6, TNF, IL-12, and IFNα (10)(11)(12), and mice deficient in the DCIR homolog Dcir1 (also known as Clec4a2) show an overexuberant expansion of DCs and develop more agingassociated or experimentally induced antibody-and T cellmediated autoimmune disorders than their WT counterpart (13)(14)(15). Intriguingly, the mechanisms responsible for these phenotypes still remain poorly understood.…”