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Published on: August 19, 2021
Macrophages form dendrite-like pseudopods to enhance bacterial ingestion
Changyuan Fan1,2,3, Xinyi Huang1,2, Jie Mei1,2,3
1Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 201203, Shanghai, China.
Abstract:
Macrophages are critical innate immune cells that exhibit remarkable adaptability during pathogen infections. However, the relationship between their morphological plasticity and physiological functions remains largely elusive. Here, we discovered an unprecedented paradigm of macrophage adaptation within a few hours upon severe Gram-negative bacterial infections, characterized by the formation of dendrite-like pseudopods (DLPs). Using in vitro, microfluidic, and in vivo infection models, we demonstrate that these pseudopods enhance bacterial uptake by expanding the macrophage searching radius, thereby bolstering host defense. Mechanistically, Toll-like receptor 4 (TLR4) activation by Gram-negative bacterial lipopolysaccharide (LPS) upregulates the expression of macrophage-specific RhoGEF and ARHGEF3 in an NF-κB-dependent manner. ARHGEF3 localizes to dendrite-like pseudopods and enhances RhoA activity. Consequently, periodic cycles of actin assembly and disassembly propel the elongation of pseudopods, whereas vimentin intermediate filaments stabilize them. Importantly, infusion of DLP-equipped macrophages into Salmonella-infected mice reduced bacterial burden and infection severity. Together, our findings underscore how the dynamic response of macrophages to massive infections can augment immune defense against pathogenic bacteria.
Insights
Macrophages form dendrite-like pseudopods (DLPs) to enhance bacterial uptake during infections. This adaptation, driven by Toll-like receptor 4 (TLR4) signaling, boosts innate immune defense against Gram-negative bacteria.
Area of Science:
- Immunology
- Cell Biology
- Microbiology
Background:
- Macrophages are key innate immune cells with adaptable functions during infections.
- The link between macrophage shape changes and their immune roles is not fully understood.
Purpose of the Study:
- To investigate the novel adaptation of macrophages forming dendrite-like pseudopods (DLPs) during Gram-negative bacterial infections.
- To elucidate the mechanisms and functional significance of DLPs in enhancing host defense.
Main Methods:
- Utilized in vitro, microfluidic, and in vivo infection models.
- Investigated Toll-like receptor 4 (TLR4) and NF-κB signaling pathways.
- Analyzed the roles of RhoGEF, ARHGEF3, RhoA, actin, and vimentin in DLP formation and function.
Main Results:
- Discovered that severe Gram-negative bacterial infections induce rapid formation of macrophage DLPs.
- Demonstrated that DLPs increase bacterial uptake by expanding the macrophage's searching area.
- Identified TLR4-NF-κB-ARHGEF3 signaling as crucial for DLP formation and RhoA activation.
- Showed that vimentin stabilizes DLPs, and actin dynamics drive their elongation.
- Confirmed that DLP-equipped macrophages reduce bacterial load in Salmonella-infected mice.
Conclusions:
- Macrophage morphological plasticity, specifically DLP formation, is a rapid adaptive response to severe bacterial infections.
- DLPs significantly enhance bacterial clearance and bolster innate immunity.
- The study reveals a novel mechanism involving TLR4-ARHGEF3-RhoA signaling in macrophage-mediated host defense.
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