Homeostatic functions of monocytes and interstitial lung macrophages are regulated via collagen domain-binding receptor LAIR1

Keerthivasan, Shilpa; Şenbabaoğlu, Yasin; Martínez‐Martín, Nadia; Husain, Bushra; Verschueren, Erik; Wong, Anne; Yang, Yeqing; Sun, Yonglian; Pham, Victoria C.; Hinkle, Trent; Oei, Yoko; Madireddi, Shravan; Corpuz, Racquel; Tam, Lucinda; Carlisle, Samantha M.; Roose‐Girma, Merone; Modrušan, Zora; Ye, Zhengmao; Koerber, James T.; Turley, Shannon J.

doi:10.1016/j.immuni.2021.06.012

Cited by 55 publications

(54 citation statements)

References 72 publications

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“…IntMϕs are intimately associated with extracellular matrix and interaction with collagen via the collagen receptor, LAIR1, appears to alter the composition of the IntMϕ pool. Notably, LAIR1 appears to regulate CSF1R expression 142 and therefore interactions with the ECM may regulate macrophage longevity, although this remains to be tested experimentally.…”

Section: Environmental Imprinting Of Lung Macrophagesmentioning

confidence: 99%

The impact of the lung environment on macrophage development, activation and function: diversity in the face of adversity

2022

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The last decade has been somewhat of a renaissance period for the field of macrophage biology. This renewed interest, combined with the advent of new technologies and development of novel model systems to assess different facets of macrophage biology, has led to major advances in our understanding of the diverse roles macrophages play in health, inflammation, infection and repair, and the dominance of tissue environments in influencing all of these areas. Here, we discuss recent developments in our understanding of lung macrophage heterogeneity, ontogeny, metabolism and function in the context of health and disease, and highlight core conceptual advances and key unanswered questions that we believe should be focus of work in the coming years.

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Section: Environmental Imprinting Of Lung Macrophagesmentioning

confidence: 99%

The impact of the lung environment on macrophage development, activation and function: diversity in the face of adversity

2022

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“…Additionally, cultivation of M1-stimulated murine or human macrophages on surfaces coated with LAIR-1 ligand peptide has been shown to result in decreased secretion of the pro-inflammatory cytokine TNFα as well as T cell attracting chemokines ( 146 ). Recently, it was demonstrated that LAIR-1 also promotes the differentiation from classical to non-classical monocytes in the bone-marrow ( 147 ). Surprisingly, this study also showed that global or myeloid-specific deletion of LAIR-1 in mice increased experimental lung metastasis of B16-F10 melanoma ( 147 ).…”

Section: Collagen Can Affect the Immune Environment In Tumorsmentioning

confidence: 99%

“…Recently, it was demonstrated that LAIR-1 also promotes the differentiation from classical to non-classical monocytes in the bone-marrow ( 147 ). Surprisingly, this study also showed that global or myeloid-specific deletion of LAIR-1 in mice increased experimental lung metastasis of B16-F10 melanoma ( 147 ). Further studies are needed to elucidate the role of LAIR-1 in other cancer models and its role in modulating anti-tumor immunity.…”

Section: Collagen Can Affect the Immune Environment In Tumorsmentioning

confidence: 99%

Immune Modulatory Properties of Collagen in Cancer

2021

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During tumor growth the extracellular matrix (ECM) undergoes dramatic remodeling. The normal ECM is degraded and substituted with a tumor-specific ECM, which is often of higher collagen density and increased stiffness. The structure and collagen density of the tumor-specific ECM has been associated with poor prognosis in several types of cancer. However, the reason for this association is still largely unknown. Collagen can promote cancer cell growth and migration, but recent studies have shown that collagens can also affect the function and phenotype of various types of tumor-infiltrating immune cells such as tumor-associated macrophages (TAMs) and T cells. This suggests that tumor-associated collagen could have important immune modulatory functions within the tumor microenvironment, affecting cancer progression as well as the efficacy of cancer immunotherapy. The effects of tumor-associated collagen on immune cells could help explain why a high collagen density in tumors is often correlated with a poor prognosis. Knowledge about immune modulatory functions of collagen could potentially identify targets for improving current cancer therapies or for development of new treatments. In this review, the current knowledge about the ability of collagen to influence T cell activity will be summarized. This includes direct interactions with T cells as well as induction of immune suppressive activity in other immune cells such as macrophages. Additionally, the potential effects of collagen on the efficacy of cancer immunotherapy will be discussed.

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“…Since LAIR-1 is able to regulate a large variety of immune cells, it is possible that the exacerbated fibrotic phenotypic observed in LAIR-1 deficient mice is driven by multiple immune cells, including monocytes, macrophages, DCs, T cells and B cells. In particular, inflammatory monocytes and tissue-resident macrophages highly express LAIR-1 and are key regulators that maintain tissue homeostasis and are important for both driving and resolving tissue repair (Carvalheiro et al ., 2020; Keerthivasan et al ., 2021; Meizlish et al ., 2021). Further studies are needed to determine which cell types are essential for LAIR-1 mediated regulation of fibrosis.…”

Section: Discussionmentioning

confidence: 99%

“…Leukocyte associated immunoglobulin-like receptor-1 (LAIR-1; CD305) is an Immunoreceptor Tyrosine-based Inhibitory Motif (ITIM)-bearing inhibitory receptor for collagen, broadly expressed on most immune cells (Lebbink et al, 2006; Meyaard et al, 1997). Activation of LAIR-1 in vitro potently inhibits diverse immune cells such as T cells, NK cells (Jansen et al, 2007; Maasho et al, 2005; Meyaard et al ., 1997; Park et al, 2020), B cells (Merlo et al, 2005) plasmacytoid dendritic cells (pDC) (Bonaccorsi et al, 2010; Son et al, 2012) and monocytes (Carvalheiro et al, 2020; Keerthivasan et al, 2021; Son and Diamond, 2015). LAIR-1 inhibitory function can be regulated at the membrane expression level and by the natural soluble agonists soluble-LAIR-1 (sLAIR-1), a shed form of LAIR-1, and LAIR-2.…”

Section: Introductionmentioning

confidence: 99%

Impaired LAIR-1-mediated immune control due to collagen degradation in fibrosis

Carvalheiro

Marut

Ramos

et al. 2021

Preprint

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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 SSc patients deposit disorganized collagen products in vitro, which are dysfunctional LAIR-1 ligands. This can be mimicked in healthy fibroblast stimulated by soluble factors that drive inflammation and fibrosis in SSc and 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 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.

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Homeostatic functions of monocytes and interstitial lung macrophages are regulated via collagen domain-binding receptor LAIR1

Cited by 55 publications

References 72 publications

The impact of the lung environment on macrophage development, activation and function: diversity in the face of adversity

The impact of the lung environment on macrophage development, activation and function: diversity in the face of adversity

Immune Modulatory Properties of Collagen in Cancer

Impaired LAIR-1-mediated immune control due to collagen degradation in fibrosis

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