Ajitha Thanabalasuriar

Cardiac macrophages (CMs) preserve homeostasis in the heart by clearing cellular debris and facilitating electrical conduction. During tissue injury, embryonically derived CMs (em-CMs) have traditionally been deemed beneficial for promoting tissue repair, whereas monocyte-derived CMs (mo-CMs) are considered detrimental, contributing to inflammation and tissue damage. However, Kasam et al. challenge this binary classification using cardiac-specific strategies to expand either em-CM or mo-CM populations. As expected, mice with cardiac-specific mo-CM expansion exhibited adverse outcomes following transverse aortic constriction (TAC). Surprisingly, mice with expanded em-CMs also showed a marked decline in cardiac function after TAC, which was associated with an unexpected interaction with mo-CMs. This deterioration was temporally regulated, occurring only if em-CMs were expanded before TAC induction. Together, these findings suggest that simplistic classification of CMs as either beneficial or harmful underestimates their complex roles in cardiac pathology, highlighting the need to reassess current views of macrophage function in heart injury.

The hyperinflammatory syndromes in critically ill patients, including trauma, sepsis, and acute lung injury, are characterized by dysregulated neutrophil responses that contribute to tissue damage and poor outcomes. Using murine models of cytokine storm induced by trauma and lung injury, we identified transforming growth factor β (TGFβ) as a central regulator of immune checkpoint in neutrophils. TGFβ signaling modulates neutrophil activation and upregulates the expression of programmed death-ligand 1 (PDL1). Disruption of TGFβ signaling during hyperinflammation restores the migratory capacity of neutrophils but leads to excessive activation, severe pulmonary tissue damage, and increased susceptibility to spontaneous bacterial infection in the lung. Mechanistically, PDL1 expression alters neutrophil behavior within lung capillaries, promoting intravascular clustering and restricting tissue infiltration. Targeted deletion of PDL1 in neutrophils reverses hyperinflammation-induced clustering, restores effective trafficking to infectious foci, and enhances host-protective immune function while limiting pathological neutrophil hyperactivation. These findings define a TGFβ-PDL1 regulatory axis that restrains the pathogenicity of neutrophils during hyperinflammation, revealing a checkpoint mechanism that balances host defense and tissue integrity.

The immune and sensory nervous systems, having evolved in parallel, communicate through shared receptors and transmitters to maintain homeostasis and respond to both external and internal disruptions. Although neural responses often confer protective benefits, they can also exacerbate inflammation during allergic reactions such as asthma. In our study, we modeled pollution-exacerbated asthma by exposing mice to ambient PM _2.5 particles alongside ovalbumin. Compared to exposure to ovalbumin alone, this co-exposure significantly increased the numbers of neutrophils and γδ T cells in bronchoalveolar lavage fluid and lung tissue, respectively. We found that silencing nociceptor neurons at the peak of inflammation using intranasal QX-314 or ablating Trpv1 -expressing neurons reduced lung neutrophil accumulation. Live in vivo intravital imaging confirmed that neuronal ablation reduced neutrophil numbers and increased their net displacement capacity. In neurons isolated from mice with pollution-exacerbated asthma, the chemical-sensing TRPA1 channel exhibited heightened sensitivity to its cognate ligand. Elevated levels of artemin were detected in the bronchoalveolar lavage fluid of pollution-exposed mice but returned to baseline in mice with ablated nociceptor neurons. Alveolar macrophages expressing the pollution-sensing aryl hydrocarbon receptor were identified as a putative source of artemin following exposure to PM _2.5 . This molecule enhanced TRPA1 responsiveness and, in turn, drove nociceptor-mediated neutrophil recruitment, revealing a novel mechanism by which lung-innervating neurons respond to air pollution in the context of allergy. Overall, our findings suggest that targeting artemin-driven pathways could provide a therapeutic strategy for controlling neutrophilic airway inflammation in asthma, a clinical condition typically refractory to treatment.

Neutrophils are the most abundant immune cells that constantly patrol or marginate inside vascular beds to support immune homeostasis. The extent to which neutrophils undergo reprogramming in response to the changes in vascular architecture and the resultant biological implications of such adaptations remain unclear. Here, we performed intravital imaging and transcriptional profiling to investigate neutrophil behavior across different tissues. Our findings revealed that neutrophils had significant deformability and spontaneous calcium signaling while navigating through the narrow pulmonary vessels. Pulmonary neutrophils exhibited unique transcriptional profiles and were specialized for proangiogenic functions. We found that the mechanosensitive ion channel Piezo-type mechanosensitive ion channel component 1 (PIEZO1) was essential for neutrophil reprogramming. Deletion of Piezo1 in neutrophils ablated the lung-specific proangiogenic transcriptional signature and impaired capillary angiogenesis in both physiological and pathological conditions. Collectively, these data show that mechanical adaptation of neutrophils within the pulmonary vasculature drives their reprogramming in the lungs and promotes pulmonary vascular homeostasis.

The path to becoming an academic researcher is winding. The trajectories and landscapes of academic success may mean many different things to each of us. There is no clear or direct path anymore. Here, I share with you my journey, giving important insights I have gathered over the years, defining what parts of this career make it worthwhile.

Parkinson’s Disease (PD) is a progressive, neurodegenerative disorder characterised by motor and non-motor symptoms. Emerging evidence suggests a link between PD and gastrointestinal dysfunction. Constipation is frequently observed years prior to development of motor dysfunction in PD, and people with inflammatory bowel disease (IBD) are more likely to develop PD. Mutations in the leucine-rich repeat kinase 2 gene ( LRRK2 ) account for approximately 1% of all PD cases and are associated with increased risk for IBD. Among them, LRRK2 Gly2019Ser (G2019S), located within the kinase domain, is the most common PD-associated mutation and increases kinase activity. It is unknown how LRRK2 mutation affects susceptibility to intestinal inflammation or pathogenesis of PD. Using single cell RNA sequencing (scRNAseq), we demonstrate that LRRK2 G2019S mutation promotes a dysregulated gene profile, especially within neutrophil, monocyte and γδ T cell populations, following Citrobacter rodentium infection in mice. Transcriptionally, LRRK2 G2019S neutrophils have a greater pro- inflammatory type I and II IFN response compared to those of WT mice. This is accompanied by an increase in neutrophil numbers in the lamina propria in LRRK2 G2019S mice. We also uncover cell-intrinsic functional defects in LRRK2 G2019S neutrophils, including increased chemotaxis, degranulation and neutrophil extracellular traps (NETosis) formation. Increased neutrophil infiltration is associated with an upregulation in Th17 immune responses, which may together contribute to the observed increase in colon pathology during infection. These findings increase our understanding of the role of PD-associated genes in immune cells and their contribution to immune dysregulation. Understanding the early perturbations driven by the LRRK2 G2019S mutation in gastrointestinal pathology may facilitate the development of biomarkers for early diagnosis and intervention in PD.

In the lower respiratory tract, the alveolar spaces are divided from the bloodstream and the external environment by only a few microns of interstitial tissue. Alveolar macrophages (AMs) defend this delicate mucosal surface from invading infections by regularly patrolling the site. AMs have three behavior modalities to achieve this goal: extending cell protrusions to probe and sample surrounding areas, squeezing the whole cell body between alveoli, and patrolling by moving the cell body around each alveolus. In this study, we found Rho GTPase, cell division control protein 42 (CDC42) expression significantly decreased after berry-flavored e-cigarette (e-cig) exposure. This shifted AM behavior from squeezing to probing. Changes in AM behavior led to a reduction in the clearance of inhaled bacteria, Pseudomonas aeruginosa . These findings shed light on pathways involved in AM migration and highlight the harmful impact of e-cig vaping on AM function.

In a world filled with microbes, some posing a threat to our body, our immune system is key to living a healthy life. The innate immune system is made of various cell types that act to guard our bodies. Unlike the adaptive immune system that has a specific response, our innate immune system encompasses cells that elicit unspecific immune responses, triggered whenever the right signals are detected. Our understanding of immunity started with the concept of our immune system only responding to “nonself” like the pathogens that invade our body. However, over the past few decades, we have learned that the immune system is more than an on/off switch that recognizes nonself. The innate immune system regularly patrols our bodies for pathogens and tissue damage. Our innate immune system not only seeks to resolve infection but also repair tissue injury, through phagocytosing debris and initiating the release of growth factors. Recently, we are starting to see that it is not just recognizing danger, our innate immune system plays a crucial role in repair. Innate immune cells phenotypically change during repair. In the context of severe injury or trauma, our innate immune system is modified quite drastically to help repair, resulting in reduced infection control. Moreover, these changes in immune cell function can be modified by sex as a biological variable. From past to present, in this overview, we provide a summary of the innate immune cells and pathways in infection and tissue repair.This article is categorized under: Immune System Diseases > Molecular and Cellular Physiology

The underlying mechanisms contributing to injury-induced infection susceptibility remain poorly understood. Here, we describe a rapid increase in neutrophil cell numbers in the lungs following induction of thermal injury. These neutrophils expressed elevated levels of programmed death ligand 1 (PD-L1) and exhibited altered gene expression profiles indicative of a reparative population. Upon injury, neutrophils migrate from the bone marrow to the skin but transiently arrest in the lung vasculature. Arrested neutrophils interact with programmed cell death protein 1 (PD-1) on lung endothelial cells. A period of susceptibility to infection is linked to PD-L1⁺ neutrophil accumulation in the lung. Systemic treatment of injured animals with an anti–PD-L1 antibody prevented neutrophil accumulation in the lung and reduced susceptibility to infection but augmented skin healing, resulting in increased epidermal growth. This work provides evidence that injury promotes changes to neutrophils that are important for wound healing but contribute to infection susceptibility.