Frontline Science: Kindlin-3 is essential for patrolling and phagocytosis functions of nonclassical monocytes during metastatic cancer surveillance

Abstract

Nonclassical monocytes maintain vascular homeostasis by patrolling the vascular endothelium, responding to inflammatory signals, and scavenging cellular debris. Nonclassical monocytes also prevent metastatic tumor cells from seeding new tissues, but whether the patrolling function of nonclassical monocytes is required for this process is unknown. To answer this question, we utilized an inducible‐knockout mouse that exhibits loss of the integrin‐adaptor protein Kindlin‐3 specifically in nonclassical monocytes. We show that Kindlin‐3‐deficient nonclassical monocytes are unable to patrol the vascular endothelium in either the lungs or periphery. We also find that Kindlin‐3‐deficient nonclassical monocytes cannot firmly adhere to, and instead “slip” along, the vascular endothelium. Loss of patrolling activity by nonclassical monocytes was phenocopied by ablation of LFA‐1, an integrin‐binding partner of Kindlin‐3. When B16F10 murine melanoma tumor cells were introduced into Kindlin‐3‐deficient mice, nonclassical monocytes showed defective patrolling towards tumor cells and failure to ingest tumor particles in vivo. Consequently, we observed a significant, 4‐fold increase in lung tumor metastases in mice possessing Kindlin‐3‐deficient nonclassical monocytes. Thus, we conclude that the patrolling function of nonclassical monocytes is mediated by Kindlin‐3 and essential for these cells to maintain vascular endothelial homeostasis and prevent tumor metastasis to the lung.

Interplay of Monocytes and T Lymphocytes in COVID-19 Severity

“…Vascular patrolling by nonclassical monocytes occurs during both steady-state and inflammation and allows surveillance against invading pathogens and maintenance of vascular endothelial homeostasis (73). We reported that the vascular endothelium is activated in mice that have nonclassical monocytes unable to patrol the vasculature due to disruptions in integrin signaling (39). We hypothesize that both nMo1 and nMo2 monocytes patrol the vasculature, but this has yet to be tested.…”

“…In contrast, CD14 dim CD16 + nonclassical monocytes (nMo) play critical roles in maintaining vascular homeostasis (39) and guard against viral pathogens (40). Shulte-Schrepping et al (14) recently reported depletion of all nonclassical monocytes in COVID-19.…”

A bi-directional dialog between vascular cells and monocytes/macrophages regulates tumor progression

“…Murine non-classical monocyte (CX3CR1 high /Ly6C lo ) differentiation and survival depend on the orphan nuclear receptor Nr4a1, and hence, Nr4a1 KO mice have drastically less nonclassical monocytes without affecting IM or macrophage population. Non-classical monocytes prevent lung metastasis formation in the PyMT breast cancer murine model or induced by LLc or B16-F10 cancer cells injected intravenously [24,185,186,200]. Indeed, more lung metastases are observed in non-classical monocyte-depleted Nr4a1 KO mice upon cancer cells injected intravenously, and this is counteracted by Ly6C lo monocyte injection [24].…”

“…Non-classical monocyte infiltration into the lungs depends on Kindlin-3 since specific Kindlin-3 deletion in non-classical monocytes diminished their lung infiltration after cancer cell injection. This diminution is associated with an increase in lung metastases [200]. The interactions between cancer cells and non-classical monocytes and subsequent cancer cell material engulfment by nonclassical monocytes depend on CX3CR1 expression in nonclassical monocytes since these processes are decreased in CX3CR1 KO mice [24].…”

The Activation and Regulation of β2 Integrins in Phagocytes and Phagocytosis

“…A recent study found that kindlin-3 directly interacts with paxillin and leupaxin through its F0 domain in the macrophage-like RAW 264.7 cell line; inhibition of kindlin-3 and paxillin/leupaxin interactions promoted cell motility and augmented phagocytosis ( 115 ). Another recent work reported that kindlin-3 was essential for patrolling function and cancer particle uptake of nonclassical monocytes during tumor metastasis to the lung ( 144 ).…”