PRRSV infection facilitates the shedding of soluble CD163 to induce inflammatory responses

• Published in: Veterinary microbiology 2024-09, Vol.296, p.110189, Article 110189
• Main Authors: Liu, Jiao, Su, Guanning, Chen, Xiaolei, Chen, Quangang, Duan, Chenrui, Xiao, Shaobo, Zhou, Yanrong, Fang, Liurong
• Format: Article
• Language: English
• Subjects: Animals; Antigens, CD - genetics; Antigens, CD - immunology; Antigens, CD - metabolism; Antigens, Differentiation, Myelomonocytic - genetics; Antigens, Differentiation, Myelomonocytic - immunology; Antigens, Differentiation, Myelomonocytic - metabolism; Cell Line; Inflammation - virology; Inflammatory response; Macrophages, Alveolar - immunology; Macrophages, Alveolar - virology; Polarization; Porcine Reproductive and Respiratory Syndrome - immunology; Porcine Reproductive and Respiratory Syndrome - virology; Porcine reproductive and respiratory syndrome virus; Porcine respiratory and reproductive syndrome virus - immunology; Receptors, Cell Surface - genetics; Receptors, Cell Surface - metabolism; Soluble CD163; Swine
• ISSN: 0378-1135; 1873-2542; 1873-2542
• DOI: 10.1016/j.vetmic.2024.110189

Porcine reproductive and respiratory syndrome (PRRS), which poses substantial threats to the global pig industry, is primarily characterized by interstitial pneumonia. Cluster of differentiation 163 (CD163) is the essential receptor for PRRSV infection. Metalloproteinase-mediated cleavage of CD163 leads to the shedding of soluble CD163 (sCD163), thereby inhibiting PRRSV proliferation. However, the exact cleavage site in CD163 and the potential role of sCD163 in inflammatory responses during PRRSV infection remain unclear. Herein, we found that PRRSV infection increased sCD163 levels, as demonstrated in primary alveolar macrophages (PAMs), immortalized PAM (IPAM) cell lines, and sera from PRRSV-infected piglets. With LC-MS/MS, Arg-1041/Ser-1042 was identified as the cleavage site in porcine CD163, and an IPAM cell line with precise mutation at the cleavage site was constructed. Using the precisely mutated IPAM cells, we found that exogenous addition of sCD163 protein promoted inflammatory responses, while mutation at the CD163 cleavage site suppressed inflammatory responses. Consistently, inhibition of sCD163 using its neutralizing antibodies reduced PRRSV infection-triggered inflammatory responses. Importantly, sCD163 promoted cell polarization from M2 to M1 phenotype, which in turn facilitated inflammatory responses. Taken together, our findings identify sCD163 as a novel proinflammatory mediator and provide valuable insights into the mechanisms underlying the induction of inflammatory responses by PRRSV infection. •PRRSV infection upregulates sCD163 levels both in vivo and in vitro.•Porcine CD163 is cleaved at the Arg-1041/Ser-1042 site to release sCD163.•sCD163 contributes to the inflammatory responses triggered by PRRSV infection.•sCD163 promotes M1 polarization to enhance inflammatory responses.