CKLF1 Disrupts Microglial Efferocytosis Following Acute Ischemic Stroke by Binding to Phosphatidylserine

Overview

Journal Cell Death Differ

Specialty Cell Biology

Date 2025 Mar 8

PMID 40057593

Authors

Ping-Long Fan

Hua-Qing Lai

Hong-Yun Wang

Kai-Chao Hu

Yuan Ruan

Jun-Rui Ye

Sha-Sha Wang

Ye Peng

Wen-Bin He

Gang Li

Xu Yan

Shi-Feng Chu

Zhao Zhang

Nai-Hong Chen

Affiliations

Soon will be listed here.

Abstract

Efferocytosis is crucial for the clearance of apoptotic cells (ACs) following acute ischemic stroke (AIS), however, its mechanism remains unclear. This study reveals that chemokine-like factor 1 (CKLF1) disrupts efferocytosis by promoting AC finding and internalization while impairing AC degradation in microglia. CKLF1 deficiency reduced the proportion of ACs and lowered levels of damage-associated molecular patterns. Mechanistically, CKLF1 binds to phosphatidylserine on apoptotic neurons/blebs, recruiting microglia to the ischemic penumbra via a C-C chemokine receptor 4 (CCR4)-dependent pathway. Apoptotic blebs with CKLF1 are engulfed into microglia, triggering the rapid production of interleukin-6 (IL6). IL6 enhances AC internalization through the signal transducer and activator of transcription 3 (STAT3)-vav guanine nucleotide exchange factor 1 (VAV1)-ras-related C3 botulinum toxin substrate 1 (RAC1) signaling cascade but simultaneously inhibits transcription factor EB (TFEB) nuclear translocation, leading to lysosomal dysfunction. This effect results in AC accumulation, compromising microglial efferocytosis efficiency and integrity. These findings uncover a novel regulatory axis induced by CKLF1, emphasizing the complex balance between AC internalization and degradation in microglial efferocytosis.

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