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Tissue repair is disturbed in fibrotic diseases like systemic sclerosis (SSc), where the deposition of large amounts of extracellular matrix components such as collagen interferes with organ function. LAIR-1 is an inhibitory collagen receptor highly expressed on tissue immune cells. We questioned whether in SSc, impaired LAIR-1-collagen interaction is contributing to the ongoing inflammation and fibrosis. We found that SSc patients do not have an intrinsic defect in LAIR-1 expression or function. Instead, fibroblasts from healthy controls and SSc patients stimulated by soluble factors that drive inflammation and fibrosis in SSc deposit disorganized collagen products in vitro, which are dysfunctional LAIR-1 ligands. This is dependent of matrix metalloproteinases and platelet-derived growth factor receptor signaling. In support of a non-redundant role of LAIR-1 in the control of fibrosis, we found that LAIR-1-deficient mice have increased skin fibrosis in response to repeated injury and in the bleomycin mouse model for SSc. Thus, LAIR-1 represents an essential control mechanism for tissue repair. In fibrotic disease, excessive collagen degradation may lead to a disturbed feedback loop. The presence of functional LAIR-1 in patients provides a therapeutic opportunity to reactivate this intrinsic negative feedback mechanism in fibrotic diseases., Competing Interests: Declaration of competing interest DF, MR and MEMG were full time employees of Boehringer Ingelheim. TRDJR was a principal investigator in the immune catalyst program of GlaxoSmith-Kline, which was an independent research program. He did not receive any financial support. Currently, TRDJR is an employee of Abbvie where he holds stock. TRDJR had no part in the design and interpretation of the study results after he started at Abbvie. LM's research lab has received financial support for investigator-initiated studies from Boehringer Ingelheim, NextCure and NGM biopharmaceuticals. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Collagens are a primary component of the extracellular matrix and are functional ligands for the inhibitory immune receptor leukocyte-associated immunoglobulin-like receptor (LAIR)-1. LAIR-2 is a secreted protein that can act as a decoy receptor by binding collagen with higher affinity than LAIR-1. We propose that collagens promote immune evasion by interacting with LAIR-1 expressed on immune cells, and that LAIR-2 releases LAIR-1-mediated immune suppression. Analysis of public human datasets shows that collagens, LAIR-1 and LAIR-2 have unique and overlapping associations with survival in certain tumors. We designed a dimeric LAIR-2 with a functional IgG1 Fc tail, NC410, and showed that NC410 increases human T cell expansion and effector function in vivo in a mouse xenogeneic-graft versus-host disease model. In humanized mouse tumor models, NC410 reduces tumor growth that is dependent on T cells. Immunohistochemical analysis of human tumors shows that NC410 binds to collagen-rich areas where LAIR-1 + immune cells are localized. Our findings show that NC410 might be a novel strategy for cancer immunotherapy for immune-excluded tumors., Competing Interests: MR, Ed, CS, AP, AS, EE, SV, JS, JB, ZC, CJ, NW, MK, LL, SL, SW, DF, LM No competing interests declared, LT LT, CS, AP, JS, JB, ZC, LL, SL and DF are employees from Nextcure. Nextcure holds a patent on NC410. (PCT/US20 17/0453 10)., (© 2021, Ramos et al.)

Alkaline phosphatase (AP) is a gate-keeper of innate immune system responses by detoxifying inflammation triggering moieties released from endogenous and external sources. We examined whether AP's broad mechanism of action constitutes a safe therapeutic, either as single agent or combined with methotrexate (MTX), for chronic inflammatory disorders, for example, rheumatoid arthritis (RA). A rat model for RA was used with repeated intra-articular methylated bovine serum albumin (mBSA) injections in 1 knee ("arthritic" knee), with the contralateral knee serving as internal control. AP (200 µg, subcut) was administered before mBSA injections (prophylactic setting) or after arthritis induction (therapeutic setting) or combined with MTX (0.3 mg/kg or 1 mg/kg; intraperitoneally). As end point of treatment outcome, macrophage infiltration in knees, liver, and spleen was assessed by immunohistochemistry (ED1 and ED2 expression), immunofluoresence (macrophage marker folate receptor-β [FRβ]), and [ 18 F]fluoro-polyethylene glycol-folate positron emission tomography (PET) (macrophage imaging) and ex vivo tissue distribution. Single-agent AP treatment and combinations with MTX were well tolerated. Both prophylactic and therapeutic AP markedly reduced synovial macrophage infiltration in arthritic knees (ED1: 3.5- to 4-fold; ED2: 3.5- to 6-fold), comparable with MTX treatment. AP-MTX combinations slightly improved on single agent effects. PET monitoring and ex vivo tissue distribution studies corroborated the impact of AP, MTX, and AP-MTX on reducing synovial macrophage infiltration. Beyond localized articular effects, AP also revealed systemic anti-inflammatory effects by a 2-fold reduction of ED1, ED2, and FRβ + macrophages in liver and spleen of arthritic rats. Collectively, single-agent AP and AP combined with MTX elicited local and systemic anti-arthritic activity in arthritic rats., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)