Immune cells are especially dependent on the proper functioning of the actin cytoskeleton, and both innate and adaptive responses rely on it. Leukocytes need to adhere not only to substrates but also to cells in order to form synapses that pass on instructions or kill infected cells. Neutrophils literally squeeze their cell body during blood extravasation and efficiently migrate to the inflammatory focus. Moreover, the development of immune cells requires the remodeling of their cytoskeleton as it depends on, among other processes, adhesive contacts and migration. In recent years, the number of reports describing cytoskeletal defects that compromise the immune system has increased immensely. Furthermore, a new emerging paradigm points toward a role for the cellular actin content as an essential component of the so-called homeostasis-altering molecular processes that induce the activation of innate immune signaling pathways. Here, we review the role of critical actin-cytoskeleton-remodeling proteins, including the Arp2/3 complex, cofilin, coronin and WD40-repeat containing protein 1 (WDR1), in immune pathophysiology, with a special focus on autoimmune and autoinflammatory traits.

In the current scenario of high antibiotic resistance, the search for therapeutic options against Pseudomonas aeruginosa must be approached from different perspectives: cell-wall biology as source of bacterial weak points and our immune system as source of weapons. Our recent study suggests that once the permeability barrier has been overcome, the activity of our cell-wall-targeting immune proteins is notably enhanced, more in mutants with impaired peptidoglycan recycling. The present work aims at analyzing the activity of these proteins [lysozyme and Peptidoglycan-Recognition-Proteins (PGLYRPs)], alone or with a permeabilizer (subinhibitory colistin) in clinical strains, along with other features related to the cell-wall. We compared the most relevant and complementary scenarios: acute (bacteremia) and chronic infections [early/late isolates from lungs of cystic fibrosis (CF) patients]. Although a low activity of lysozyme/PGLYRPs per se (except punctual highly susceptible strains) was found, the colistin addition significantly increased their activity regardless of the strains’ colistin resistance levels. Our results show increased susceptibility in late CF isolates, suggesting that CF adaptation renders P. aeruginosa more vulnerable to proteins targeting the cell-wall. Thus, our work suggests that attacking some P. aeruginosa cell-wall biology-related elements to increase the activity of our innate weapons could be a promising therapeutic strategy.

Cells have evolved mechanisms that allow them to respond to DNA damage to preserve genomic integrity and maintain tissue homeostasis. These responses include the activation of the cell cycle checkpoints and the repair mechanisms or the induction of apoptosis that eventually will eliminate damaged cells. These “life” vs. “death” decisions differ depending on the cell type, stages of development, and the proliferation status of the cell. The apoptotic response after DNA damage is of special interest as defects in its induction could contribute to tumorigenesis or the resistance of cancer cells to therapeutic agents such as radiotherapy. Multiples studies have elucidated the molecular mechanisms that mediate the activation of the DNA damage response pathway (DDR) and specifically the role of p53. However, much less is known about how the different cellular responses such as cell proliferation control and apoptosis are coordinated to maintain tissue homeostasis. Another interesting question is how the differential apoptotic response to DNA damage is regulated in distinct cell types. The use of Drosophila melanogaster as a model organism has been fundamental to understand the molecular and cellular mechanisms triggered by genotoxic stress. Here, we review the current knowledge regarding the cellular responses to ionizing radiation as the cause of DNA damage with special attention to apoptosis in Drosophila: how these responses are regulated and coordinated in different cellular contexts and in different tissues. The existence of intrinsic mechanisms that might attenuate the apoptotic pathway in response to this sort of DNA damage may well be informative for the differences in the clinical responsiveness of tumor cells after radiation therapy.

Synergistic and antagonist drug interactions of drug combinations against Leishmania drug sensitive and resistant cell lines.