Myeloid Zfhx3 deficiency protects against hypercapnia-induced suppression of host defense against influenza A virus

Casalino-Matsuda, S. Marina1,6; Chen, Fei1; Gonzalez-Gonzalez, Francisco J.1; Matsuda, Hiroaki2; Nair, Aisha1; Abdala-Valencia, Hiam1; Budinger, G. R. Scott1,3; Dong, Jin-Tang4; Beitel, Greg J.5; Sporn, Peter H. S.1,3

2024-02-22

10.1172/jci.insight.170316

JCI INSIGHT   影响因子和分区

2379-3708

Hypercapnia, elevation of the partial pressure of CO2 in blood and tissues, is a risk factor for mortality in patients with severe acute and chronic lung diseases. We previously showed that hypercapnia inhibits multiple macrophage and neutrophil antimicrobial functions and that elevated CO2 increases the mortality of bacterial and viral pneumonia in mice. Here, we show that normoxic hypercapnia downregulates innate immune and antiviral gene programs in alveolar macrophages (AMos). We also show that zinc finger homeobox 3 (Zfhx3) - a mammalian ortholog of zfh2, which mediates hypercapnic immune suppression in Drosophila - is expressed in mouse and human macrophages. Deletion of Zfhx3 in the myeloid lineage blocked the suppressive effect of hypercapnia on immune gene expression in AMos and decreased viral replication, inflammatory lung injury, and mortality in hypercapnic mice infected with influenza A virus. To our knowledge, our results establish Zfhx3 as the first known mammalian mediator of CO2 effects on immune gene expression and lay the basis for future studies to identify therapeutic targets to interrupt hypercapnic immunosuppression in patients with advanced lung disease.

SCI

英语

其他

NIH["I01 CX002350","U19AI35964","P01AG049665","P01AG04966506S1","R01HL147575"] ; Department of Veterans Affairs["P30-CA060553","I01 CX001777"] ; NCI CCSG[P30CA060553] ; NCI Cancer Center Support Grant[P01AG049665] ; null[R01HL131745]

Research & Experimental Medicine

Medicine, Research & Experimental

WOS:001170727400001

AMER SOC CLINICAL INVESTIGATION INC

Web of Science

1.Northwestern Univ, Feinberg Sch Med, Div Pulm & Crit Care Med, Chicago, IL USA
2.Wilbur Wright Coll, Dept Phys Sci & Engn, Chicago, IL USA
3.Jesse Brown Vet Affairs Med Ctr, Res & Serv, Chicago, IL USA
4.Southern Univ Sci & Technol, Sch Med, Dept Human Cell Biol & Genet, Shenzhen, Peoples R China
5.Northwestern Univ, Weinberg Coll Arts & Sci, Dept Mol Biosci, Evanston, IL USA
6.303 E Super St,Simpson Querrey 5-405, Chicago, IL 60611 USA

Casalino-Matsuda, S. Marina,Chen, Fei,Gonzalez-Gonzalez, Francisco J.,et al. Myeloid Zfhx3 deficiency protects against hypercapnia-induced suppression of host defense against influenza A virus[J]. JCI INSIGHT,2024,9(4).

Casalino-Matsuda, S. Marina.,Chen, Fei.,Gonzalez-Gonzalez, Francisco J..,Matsuda, Hiroaki.,Nair, Aisha.,...&Sporn, Peter H. S..(2024).Myeloid Zfhx3 deficiency protects against hypercapnia-induced suppression of host defense against influenza A virus.JCI INSIGHT,9(4).

Casalino-Matsuda, S. Marina,et al."Myeloid Zfhx3 deficiency protects against hypercapnia-induced suppression of host defense against influenza A virus".JCI INSIGHT 9.4(2024).