Blocking elevated p38 MAPK restores efferocytosis and inflammatory resolution in the elderly

Immunesenescence: A Predisposing Risk Factor for the Development of COVID-19?

“…Since vimentin was recently found to be expressed on the surface of senescent lung fibroblasts ( 221 ), and the fact that SARS-CoV-1 and SARS-CoV-2 utilize the same mechanism of attachment to host cells, a number of groups have proposed increased SARS-CoV-2 replication would occur in individuals with a high senescent cell burden ( 222 – 224 ). Thus, an increased presence of senescent cells may predispose to the development of severe COVID-19 via two mechanisms: ( 1 ) reduced immune cell clearance by contributing to the aforementioned inflammation-induced suppression of innate and adaptive immunity ( 204 , 205 , 225 ) and ( 3 ) increasing viral load by acting as a site of enhanced SARS-CoV-2 replication. Interestingly, a number of clinical trials assessing the therapeutic benefit of drugs that directly eliminate senescent cells or suppress their SASP are already underway in patients with COVID-19 ( 223 , 226 ).…”

“…A co-ordinated multi-step program that involves the clearance of apoptosed neutrophils by macrophages (efferocytosis) and the generation of specialized pro-resolving lipid mediators (SPMs), the resolution of inflammatory responses is an active process that protects against unwarranted tissue damage ( 252 ). Whilst we await data relating specifically to features of the resolution phase in SARS-CoV-2-infected patients, a series of murine and human-based studies have shown aging ( 97 , 225 , 253 ), obesity ( 254 , 255 ) and T2D ( 254 , 256 ) are all associated with delayed resolution of inflammatory responses.…”

“…Attributed to a p38 MAPK driven reduction in the expression of T-cell immunoglobulin mucin protein 4 (TIM-4), a receptor expressed by macrophages that recognizes phosphatidylserine on the surface of apoptosed neutrophils, De Maeyer and colleagues recently demonstrated an age-associated impairment in efferocytosis ( 225 ). In a human dermal model of acute sterile inflammation, this defect in efferocytosis resulted in the accumulation of annexin V + neutrophils and delayed resolution ( 225 ).…”

“…Attributed to a p38 MAPK driven reduction in the expression of T-cell immunoglobulin mucin protein 4 (TIM-4), a receptor expressed by macrophages that recognizes phosphatidylserine on the surface of apoptosed neutrophils, De Maeyer and colleagues recently demonstrated an age-associated impairment in efferocytosis ( 225 ). In a human dermal model of acute sterile inflammation, this defect in efferocytosis resulted in the accumulation of annexin V + neutrophils and delayed resolution ( 225 ). Mirroring these observations, reduced clearance of apoptosed cells by macrophages has been reported in the experimental settings of obesity ( 97 , 254 , 257 ) and diabetes ( 254 , 256 , 258 ), with decreased PI3-K signaling ( 257 ) and elevated PGE 2 levels in inflammatory exudate ( 254 ) identified as potential underlying causes.…”

“…Based in part on the fact that in these models administration of PD1 improved survival rates and pulmonary function ( 260 ), SPM treatment has been proposed as a therapy by which to promote the resolution of lung inflammation and reduce tissue damage in COVID-19 patients ( 261 ). Importantly, treatment regimens that include exogenous application of SPMs and inhibition of P38 MAPK have been shown in human and animal models to overcome the delay in inflammatory resolution that occurs as a consequence of aging and the presence of co-morbidities ( 225 , 253 , 256 ). Thus, it appears that resolution of inflammation can be manipulated in groups at high risk of severe COVID-19.…”