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Phenotypic screens for SIRPA expression reveal RAB21 as a general regulator of macrophage surface identity

ABSTRACT: Phenotypic screens for SIRPA expression reveal RAB21 as a general regulator of macrophage surface identity

PROVIDER: PRJNA1262991 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR33565700.fastq.gz	Fastqsanger.gz
	SRR33565701.fastq.gz	Fastqsanger.gz
	SRR33565702.fastq.gz	Fastqsanger.gz
	SRR33565703.fastq.gz	Fastqsanger.gz
	SRR33565704.fastq.gz	Fastqsanger.gz

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Phenotypic screens for SIRPA expression reveal RAB21 as a general regulator of macrophage surface identity

Project description:Factors influencing the macrophage surfaceome define macrophage identity and behaviour. Here, we use genome-wide phenotypic screens to identify genes affecting the accessibility and surface expression of macrophage SIRPA. Our data are consistent with previous evidence but also implicate QPCTL in cis CD47-SIRPA interactions. We also identify endolysosomal factors encoded by RAB21 and members of the CCC and WASH complexes as modulators of SIRPA expression. Surface immunophenotyping and surfaceome profiling show that inactivation of either Sirpa or Rab21 remodels cell surface protein expression. In contrast to Sirpa, Rab21 appears to be a general regulator of established macrophage cell surface markers. Perturbation of RAB21/Rab21 reduced Fc gamma receptor expression, leading to decreased uptake of antibody-nanoparticle conjugates and impaired phagocytosis of opsonized cells. To summarize, our study describes circuitry controlling SIRPA expression on macrophages and reveals a conserved RAB21-dependent trafficking pathway that has a role in modelling the cell surface of macrophages.

2025-06-03 | GSE297202 | GEO

Phenotypic screens for SIRPa expression reveal RAB21 as a general regulator of macrophage surface identity

Project description:Through CRISPR screening we found that RAB21 modulates surface SIRPa expression in macrophage models. Here, to confirm our screen results in an unbiased and high-throughput manner we performed cell surfaceome profiling of RAW264.7 cells that lack SIRPa or RAB21. Beyond confirming our screen results, we discovered dramatic cell surfaceome changes in the absence of RAB21 for several surface receptors, including Fc gamma receptors.

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SIRPa agonist antibody treatment ameliorates experimental arthritis and colitis [sequencing]

Project description:The innate immune system is finely tuned to enable rapid response to pathogenic stimuli but keep quiescent during tissue homeostasis.Balance of activating and inhibitory signaling sets a threshold for immune activation. Signal regulatory protein (SIRPa) is an immune inhibitory receptor expressed by myeloid cells and interacts with CD47 to inhibit immune cell phagocytosis, migration, and activation. Despite the progress of SIRPa and CD47 antagonist antibodies to promote anti-cancer immunity, it is not yet known whether therapeutic SIRPa receptor agonism could restrain excessive autoimmune inflammation in the context of autoimmunity. Here, we reported that increased neutrophil- and monocyte-associated genes including SIRPA in inflamed tissues biopsies of rheumatoid arthritis and inflammatory bowel diseases, and elevated SIRPA in colonic biopsies is associated with treatment refractory ulcerative colitis patients. We next identified a novel agonistic anti-SIRPa antibody that exhibited potent anti-inflammatory effects in reducing neutrophil and monocytes chemotaxis and tissue infiltration. In preclinical models of arthritis and colitis, anti-SIRPa agonistic antibody ameliorates autoimmune joint inflammation and inflammatory colitis through reducing neutrophils and monocytes in tissues. Our work provides a proof-of-concept for SIRPa receptor agonism for suppressing excessive innate immune activation and autoimmune inflammatory therapeutic treatment

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SIRPa agonist antibody treatment ameliorates experimental arthritis and colitis [array]

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2024-05-13 | GSE267243 | GEO

SIRPa ablation overcomes exhaustion and enhances the antibody- and CAR-mediated antitumor activities of iPSC-derived CAR Macrophages

Project description:SIRPa-CD47 “don’t eat me” checkpoint axis plays a critical role in defining anti-tumor activities of macrophages within the tumor microenvironment. However, targeting this axis with anti-CD47 antibodies to improve anti-tumor responses in clinical trials has proven challenging. Here, we demonstrated that iPSC-derived macrophages (iMacs) with ablated SIRPa yield a superior antitumor effect in conjunction with cancer-targeted antibodies (Ab) or chimeric antigen receptor (CAR) against a variety of CD47-expressing tumors in vitro. Moreover, SIRPA-KO protected macrophages from Ab- or CAR-driven exhaustion, allowing for efficient phagocytosis of tumors after multiple rounds of cancer re-challenges. Ablation of SIRPa in iMacs improved survival of mice grafted ovarian carcinoma and treated with anti-HER2 Abs, while anti-GD2 CAR iMacs with KO SIRPA demonstrated reduction of initial tumor burden in mice with metastatic neuroblastoma xenograft. Overall, our studies support the feasibility of using the iPSC platform to generate SIRPα-ablated iMacs that are resistant to CD47-mediated inhibition for therapeutic applications.

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