| First Author | Loh JT | Year | 2022 |
| Journal | Front Immunol | Volume | 13 |
| Pages | 996637 | PubMed ID | 36172386 |
| Mgi Jnum | J:336030 | Mgi Id | MGI:7342484 |
| Doi | 10.3389/fimmu.2022.996637 | Citation | Loh JT, et al. (2022) Dok3 restrains neutrophil production of calprotectin during TLR4 sensing of SARS-CoV-2 spike protein. Front Immunol 13:996637 |
| abstractText | Increased neutrophils and elevated level of circulating calprotectin are hallmarks of severe COVID-19 and they contribute to the dysregulated immune responses and cytokine storm in susceptible patients. However, the precise mechanism controlling calprotectin production during SARS-CoV-2 infection remains elusive. In this study, we showed that Dok3 adaptor restrains calprotectin production by neutrophils in response to SARS-CoV-2 spike (S) protein engagement of TLR4. Dok3 recruits SHP-2 to mediate the de-phosphorylation of MyD88 at Y257, thereby attenuating downstream JAK2-STAT3 signaling and calprotectin production. Blocking of TLR4, JAK2 and STAT3 signaling could prevent excessive production of calprotectin by Dok3(-/-) neutrophils, revealing new targets for potential COVID-19 therapy. As S protein from SARS-CoV-2 Delta and Omicron variants can activate TLR4-driven calprotectin production in Dok3(-/-) neutrophils, our study suggests that targeting calprotectin production may be an effective strategy to combat severe COVID-19 manifestations associated with these emerging variants. |
