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Updated: Sep 2, 2025
Depletion and Reconstitution of Macrophages in Mice
Published on: August 1, 2012
Cysteinyl Maresins Reprogram Macrophages to Protect Mice from Streptococcus pneumoniae after Influenza A Virus
Luciana P Tavares1,2, Thayse R Brüggemann1, Rafael M Rezende3
1Pulmonary and Critical Care Medicine Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Abstract:
Influenza A virus (IAV) infections are a leading cause of mortality worldwide. Excess mortality during IAV epidemics and pandemics is attributable to secondary bacterial infections, particularly pneumonia caused by Streptococcus pneumoniae. Resident alveolar macrophages (rAMs) are early responders to respiratory infections that coordinate initial host defense responses. Maresin conjugates in tissue regeneration (MCTRs) are recently elucidated cysteinyl maresins that are produced by and act on macrophages. Roles for MCTRs in responses to respiratory infections remain to be determined. Here, IAV infection led to transient decreases in rAM numbers. Repopulated lung macrophages displayed transcriptional alterations 21 days post-IAV with prolonged susceptibility to secondary pneumococcal infection. Administration of a mix of MCTR1 to 3 or MCTR3 alone post-IAV decreased lung inflammation and bacterial load 48 and 72 h after secondary pneumococcal infection. MCTR-exposed rAMs had increased migration and phagocytosis of Streptococcus pneumoniae, reduced secretion of CXCL1, and a reversion toward baseline levels of several IAV-induced pneumonia susceptibility genes. Together, MCTRs counter regulated post-IAV changes in rAMs to promote a rapid return of bacteria host defense. IMPORTANCE Secondary bacterial pneumonia is a serious and common complication of IAV infection, leading to excess morbidity and mortality. New host-directed approaches are needed to complement antibiotics to better address this important global infectious disease. Here, we show that harnessing endogenous resolution mechanisms for inflammation by exogenous administration of a family of specialized proresolving mediators (i.e., cys-MCTRs) increased macrophage resilience mechanisms after IAV to protect against secondary infection from Streptococcus pneumoniae.
Insights
Maresin conjugates in tissue regeneration (MCTRs) enhance macrophage function after influenza A virus (IAV) infection. This boosts defense against secondary Streptococcus pneumoniae infections, reducing lung inflammation and bacterial load.
Area of Science:
- Immunology
- Infectious Diseases
- Respiratory Medicine
Background:
- Influenza A virus (IAV) infection increases mortality, often due to secondary bacterial pneumonia from Streptococcus pneumoniae.
- Resident alveolar macrophages (rAMs) are crucial for initial host defense against respiratory infections.
- Maresin conjugates in tissue regeneration (MCTRs) are specialized proresolving mediators acting on macrophages, but their role in respiratory infections is unknown.
Purpose of the Study:
- To investigate the role of MCTRs in host defense following IAV infection and secondary pneumococcal challenge.
- To determine if MCTR administration can mitigate the negative impacts of IAV on macrophage function and susceptibility to bacterial infection.
Main Methods:
- Induction of IAV infection in a model system, followed by secondary challenge with Streptococcus pneumoniae.
- Assessment of lung macrophage populations, transcriptional profiles, and inflammatory markers.
- Administration of MCTR1-3 mix or MCTR3 alone post-IAV infection.
- Evaluation of macrophage migration, phagocytosis, and bacterial load in the lungs.
Main Results:
- IAV infection transiently reduced rAM numbers and altered lung macrophage gene expression, increasing susceptibility to pneumococcal infection.
- Post-IAV administration of MCTRs decreased lung inflammation and Streptococcus pneumoniae load.
- MCTRs enhanced rAM migration and phagocytosis of bacteria, reduced CXCL1 secretion, and normalized IAV-induced susceptibility genes.
Conclusions:
- MCTRs counteract IAV-induced alterations in rAMs, promoting a faster return to effective bacterial host defense.
- Exogenous administration of cys-MCTRs represents a potential host-directed therapeutic strategy to protect against secondary bacterial pneumonia post-IAV infection.
