Monocyte-Derived Macrophages Exhibit Differences in Inflammatory Gene Expression Based on Sex and Cannabis Use Pattern of the Donor: A Post-Hoc Analysis

The human immune system is a vast, intricate network of cells that patrol the body, constantly scanning for threats and managing inflammation. Among these sentinels are macrophages, large cells that act as both cleaners and messengers. They engulf debris and bacteria, but they also release chemical signals that can either calm an injury or, if left unchecked, cause chronic swelling that damages healthy tissue. In recent years, scientists have become increasingly interested in how these cells behave differently depending on whether they come from a person assigned male or female at birth. These differences are not just about hormones; they appear to be woven into the very genetic instructions that tell the cells how to react. At the same time, millions of people use cannabis, a plant containing compounds that can alter how the immune system functions. While we know that cannabis can change inflammation, we do not fully understand if it changes the immune response in men and women in the same way. This question is particularly urgent for people living with HIV, where even when the virus is controlled by medication, low-level inflammation often persists, contributing to long-term health issues.

A team of researchers at the University of California San Diego set out to explore this intersection of sex, cannabis use, and immune function. They focused on monocyte-derived macrophages, which are immune cells grown in a laboratory from blood samples donated by people with and without HIV. The researchers wanted to see if the genetic instructions inside these cells differed between men and women, and whether those instructions changed based on the donor's history of cannabis use. Specifically, they looked at two key systems within the cells: one that acts like an alarm bell to trigger inflammation, and another that acts like a brake to help the cell return to a calm state. They took cells from donors who had never used cannabis and those who used it regularly, then exposed the cells in the lab to inflammatory triggers and to compounds found in cannabis, watching closely to see how the cells' genes responded.

The study began by examining the cells before any treatment, looking for natural differences between the sexes. The researchers found that cells from female donors carried higher baseline levels of genetic instructions for two specific inflammatory markers compared to cells from male donors. One of these markers, a protein called TREM2, helps the cell manage damage and return to a stable state, while the other, IL-18, is a signal that promotes inflammation. The cells from women showed about 57 percent more of the TREM2 instructions and 53 percent more of the IL-18 instructions than the cells from men. This suggests that, even before any external trigger, the immune cells of women are set to a slightly different level of readiness and regulation than those of men. The researchers also noted that the cells from women showed much more variation from one donor to another, hinting that female immune responses might be more diverse or sensitive to individual factors.

Next, the team introduced specific substances to the cells to see how they reacted. They added a known inflammatory trigger, along with two major compounds found in cannabis: tetrahydrocannabinol, which is responsible for the psychoactive effects, and cannabidiol, which is non-intoxicating. When the cells were stimulated, both men and women showed strong reactions, but the magnitude of the response differed. In cells from male donors, the combination of the inflammatory trigger and cannabidiol led to a particularly sharp increase in the production of IL-1β, a potent inflammatory signal. This suggests that when male immune cells are already in a state of inflammation, the presence of cannabidiol might amplify the signal rather than dampen it, at least in this specific laboratory setting. The cells from female donors also responded to the treatments, but the pattern of their reaction was distinct, showing that the sex of the donor fundamentally shapes how the cell interprets and reacts to these chemical signals.

The researchers then looked at how the history of cannabis use in the donor affected the cells. They compared cells from people who had never used cannabis with those who used it regularly. In male donors, a history of cannabis use was linked to lower levels of instructions for the inflammatory alarm system and the calming receptor. Essentially, the cells from men who used cannabis seemed to have dialed down their baseline inflammatory machinery. However, this pattern did not hold true for women. In female donors, cannabis use was not associated with lower levels of these genes. Instead, women who used cannabis showed significantly higher levels of the IL-18 inflammatory signal compared to men who used cannabis. This finding highlights a crucial divergence: the same habit of cannabis use appears to reset the immune system's baseline in opposite directions depending on whether the donor is male or female.

The study also revealed that the interaction between inflammation and cannabis compounds is complex and sex-dependent. When cells were treated with a combination of the inflammatory trigger and cannabis compounds, the response was not uniform. For instance, in male donors who did not use cannabis, cannabidiol reduced the inflammatory alarm signals. But in male donors who were regular cannabis users, this dampening effect disappeared, and the cells responded differently to the combination. In female donors, the response was heavily influenced by whether they were users or non-users, with the most robust increases in inflammatory signals occurring when the cells were hit with both the inflammatory trigger and cannabidiol. The researchers observed that the cells from women generally showed a more variable and context-dependent reaction, whereas the cells from men showed more consistent, though distinct, patterns of suppression or amplification based on their cannabis history.

Despite these clear patterns, the researchers were careful to note the limits of their findings. The study relied on cells grown in a dish, which may not perfectly mimic how these cells behave inside the human body. Additionally, the group of female donors living with HIV was very small, which made it difficult to draw firm conclusions about how the virus itself interacts with sex and cannabis use. The study also did not measure hormone levels directly, so while the differences are clearly linked to biological sex, the exact hormonal mechanisms driving them remain a hypothesis for future research. The authors emphasize that these results suggest a relationship rather than proving a definitive cause-and-effect, and they call for larger studies to confirm whether these sex-specific differences hold true in the broader population.

Ultimately, this work provides a clearer picture of how the immune system is not a one-size-fits-all machine. It shows that the biological sex of a person influences the baseline settings of their immune cells and how those cells react to common substances like cannabis. For men, cannabis use seemed to lower certain inflammatory markers, while for women, it appeared to elevate others. These differences suggest that when doctors or researchers interpret immune markers or consider treatments involving cannabinoids, they cannot simply apply a single rule to everyone. The sex of the patient matters, and the history of their substance use matters in a way that is specific to their biology. As science moves forward, understanding these nuances will be essential for developing treatments that work effectively for everyone, regardless of whether they are male or female.