No abstract

As of January 25, 2022, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak has caused more than 340 million infections with over 5.5 million deaths. [1] Coronavirus disease 2019 (COVID-19) patients may develop various clinical manifestations, including severe acute pulmonary disease, [2][3][4] hepatic dysfunction, [3,4] kidney injury, [4] heart damage, [3,4] gastrointestinal, [5] pancreatic symptoms, [6] and olfactory dysfunction. [7] However, due to the lagged, yet possibly long-lasting effects, [8] the impact of COVID-19 on the skeleton system has not been well characterized. Bone is the major reservoir for body calcium and phosphorus. [9] Preliminary clinical data have uncovered COVID-19-associated calcium metabolic disorders and osteoporosis. [10,11] Importantly, severe COVID-19 patients are found to have decreased blood calcium and phosphorus levels, in comparison with moderate COVID-19 patients. [12] These observations suggest a possible link between SARS-CoV-2 infection and damage in the skeleton system. In humans, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can cause medical complications across various tissues and organs. Despite the advances to understanding the pathogenesis of SARS-CoV-2, its tissue tropism and interactions with host cells have not been fully understood. Existing clinical data have revealed disordered calcium and phosphorus metabolism in Coronavirus Disease 2019 (COVID-19) patients, suggesting possible infection or damage in the human skeleton system by SARS-CoV-2. Herein, SARS-CoV-2 infection in mouse models with wildtype and beta strain (B.1.351) viruses is investigated, and it is found that bone marrow-derived macrophages (BMMs) can be efficiently infected in vivo. Single-cell RNA sequencing (scRNA-Seq) analyses of infected BMMs identify distinct clusters of susceptible macrophages, including those related to osteoblast differentiation. Interestingly, SARS-CoV-2 entry on BMMs is dependent on the expression of neuropilin-1 (NRP1) rather than the widely recognized receptor angiotensin-converting enzyme 2 (ACE2). The loss of NRP1 expression during BMM-to-osteoclast differentiation or NRP1 neutralization and knockdown can significantly inhibit SARS-CoV-2 infection in BMMs. Importantly, it is found that authentic SARS-CoV-2 infection impedes BMM-to-osteoclast differentiation. Collectively, this study provides evidence for NRP1-mediated SARS-CoV-2 infection in BMMs and establishes a potential link between disturbed osteoclast differentiation and disordered skeleton metabolism in COVID-19 patients.

Macrophages are a group of heterogeneous cells widely present throughout the body. Under the influence of their specific environments, via both contact and noncontact signals, macrophages integrate into host tissues and contribute to their development and the functions of their constituent cells. Mitochondria are essential organelles that perform intercellular transfers to regulate cell homeostasis. Our review focuses on newly discovered roles of mitochondrial transfers between macrophages and surrounding cells and summarizes emerging functions of macrophages in transmitophagy, metabolic regulation, and immune defense. We also discuss the negative influence of mitochondrial transfers on macrophages, as well as current therapies targeting mitochondria in macrophages. Regulation of macrophages through mitochondrial transfers between macrophages and their surrounding cells is a promising therapy for various diseases, including cardiovascular diseases, inflammatory diseases, obesity, and cancer.